Natural Killer (NK) cells, which account for up to 15% of peripheral blood lymphocytes, are an integral component of innate immunity. NK cells can lyse tumor and virally infected cells without prior sensitization while sparing normal cells expressing adequate levels of major histocompatibility complex class-I (MHC-I) antigens. This function is under the control of a heterogeneous family of inhibitory NK receptors (iNKRs) that bind specifically to certain allelic forms of MHC-1 molecules. Loss or diminution of levels of MHC-1 expression on tumor cells or virally infected cells results in reduced iNKRs engagement, which in turn triggers activating NK receptors and co-receptors to lyse such target cells. It is well documented that NK cells isolated from HIV-infected individuals are reduced in their ability to kill HIV infected cells, as well as tumor cell lines in vitro. We have previously demonstrated that 1) the expression of the majority of iNKRs was either maintained or significantly increased on NK cells of viremic infected patients, 2) the expression and cytolytic activity of natural cytotoxicity receptors (NCRs), NKp46, NKp30 and NKp44 was markedly impaired in NK cells of viremic infected individuals, 3) a subset of NK cells exhibiting the CD56neg/CD16pos phenotype was expanded in viremic HIV infected patients, and 4) NK cell abnormalities were restored in patients receiving clinically successful antiretroviral therapy (ARV). We have advanced our understanding of NK cells in the past year by further characterizing the phenotypic and functional properties of the CD56neg/CD16pos NK subset isolated from viremic HIV-infected individuals. We have demonstrated that the levels of iNKRs were significantly higher on CD56neg/CD16pos NK cells compared to that of CD56pos/CD16pos NK cells. We have also demonstrated that the levels of NCRs were significantly lower on CD56neg/CD16pos NK cells compared to those of CD56pos/CD16pos NK cells. Finally, we have demonstrated a significant reduction in production of IFN-g, TNF-a and GM-CSF in HIV infected viremic patients relative to that of uninfected individuals. These data suggest that the dramatic expansion of the CD56neg/CD16pos NK cell subset largely accounts for the impaired function of the NK cells in viremic infected individuals.